A series of isopropylsulfonyl-substituted 2,4-diarylaminopyrimidine derivatives were designed and synthesized as FAK inhibitors to evaluate their biological activity against pancreatic cancer. One of the most promising compound, 9h, effectively interfered with FAK-mediated phosphorylation and suppressed the proliferation of human pancreatic cancer AsPC-1 cells with half maximal inhibitory concentration (IC₅₀) values of 0.1165 nM and 0.1596 μM, respectively. In addition, 9h also exhibited relatively low toxicity against immortalized normal human liver L-02 cells, indicating its low hepatotoxicity at an equivalent dosage. Furthermore, the elucidation of the mechanism of action revealed that compound 9h effectively inhibited cell migration and inhibited the proliferation of AsPC-1 by blocking the cell cycle at the G2/M phase. Moreover, 9h also demonstrated efficacy in inhibiting tumor growth in a murine AsPC-1 cell xenograft model at the dosage of 10 mg/kg without losing noticeable body weight. All these findings provide important clues for the identification of potent FAK inhibitors.

设计并合成了一系列异丙基磺酰基取代的 2,4-二芳基氨基嘧啶衍生物作为 FAK 抑制剂，以评估其对胰腺癌的生物活性。最有希望的化合物之一9h可有效干扰 FAK 介导的磷酸化并抑制人胰腺癌 AsPC-1 细胞的增殖，其半数最大抑制浓度 (IC ₅₀ ) 值分别为 0.1165 nM 和 0.1596 μM。此外，9h对永生化正常人肝L-02细胞的毒性也相对较低，表明其在同等剂量下的肝毒性较低。此外，对作用机制的阐明揭示了化合物9h通过阻断 G2/M 期的细胞周期，有效抑制细胞迁移并抑制 AsPC-1 的增殖。此外，9h还证明了在小鼠 AsPC-1 细胞异种移植模型中以 10 mg/kg 的剂量抑制肿瘤生长的功效，而不会明显减轻体重。所有这些发现为鉴定有效的 FAK 抑制剂提供了重要线索。